Mutations in oncogenes and tumor suppressor genes in animal and human tumors may give important clues as to the exposures that led to the tumors. For rodent neoplasms that are pathologically similar to the corresponding human cancer, the rodent disease may be used to model the cellular events involved and to study prevention and therapy. Currently, we are focusing on the K-ras gene in lung cancer. In studies of the role of the oncogene K-ras in genesis of adenocarcinoma of the lung, we are utilizing a mouse model, including tumors induced in vivo, and normal immortalized and transformed alveolar type 2 cells in vitro. An important question is why mutant K-ras is actively oncogenic, since wild-type K-ras is a tumor suppressor. An answer to this question could aid in prevention of up to 50% of human lung adenocarcinomas, and an even higher percentage of cancers of the colon and pancreas. We have been pursuing the hypothesis that high activity of mutant K-ras leads to generation of reactive oxygen species, which damage DNA and so lead to malignant transformation. We have expressed mutant K-ras in nontransformed lung epithelial cells, and demonstrated increase in several forms of reactive oxygen, including peroxides and superoxide, and DNA damage. Sources of the reactive oxygen include the lung cancer-associated enzyme COX2, and NADPH oxidase. Induction of these toxic effects is followed shortly by upregulation of anti-oxidant enzymes, including superoxide dismutase and peroxidoredoxins, then damping out of the damage. Thus anti-oxidant defenses is an important aspect of the carcinogenic process here. These parameters are also being studied in human lung adenocarcinonma cell lines, and primary human lung cancers are being collected via the Human Cooperative Tissue Network. Results will have applicability for prevention and possibly therapy of human lung cancer.